The synthesis and use of substituted imidazoles in pharmaceutical preparations useful in treating atherosclerosis and in lowering serum cholesterol is known. For example, EP 0 372 445 Al discloses an antihypercholesterolemic agent having the formula: ##STR1## wherein R.sup.1 and R.sup.2 are various hydrocarbyl or heteroaryl groups;
R.sup.3 is hydrogen or various hydrocarbyl groups; PA1 X is S(O).sub.r, O, NR.sup.5, or CH.sub.2, wherein r is 0-2 and R.sup.5 is H, C.sub.1 -C.sub.6 alkyl, or benzyl; PA1 A is C.sub.2 -C.sub.10 alkyl, C.sub.3 -C.sub.10 branched alkyl, C.sub.3 -C.sub.10 alkenyl, or C.sub.3 -C.sub.10 alkynyl; PA1 Y is O, S, or H.sub.2 ; PA1 Z is NHR.sup.4, OR.sup.4, or R.sup.4, wherein R.sup.4 is various substituted and unsubstituted hydrocarbyl groups; and PA1 R.sup.6 is hydrogen or various substituted and unsubstituted hydrocarbyl groups. (See EP 0 372 445 Al, pp. 5-7). PA1 (III') is an amine, PA1 (IV) is an omega hydroxyalkanamide, PA1 (IV') is an alkanesulfonic acid halide or anhydride, PA1 (V) is an omega-alkanesulfonoxyalkanamide, PA1 R.sup.7 is selected from the group consisting of substituted or unsubstituted lower alkyls of 1-4 carbon atoms such as methyl, trifluoromethyl, ethyl, propyl, isopropyl. PA1 R.sup.8 and R.sup.9 each independently represents hydrogen, alkyl, alkenyl, cyclic alkyl, cyclic alkenyl, phenyl optionally substituted with 1 to 3 groups selected from C.sub.1 -C.sub.4 alkyl or alkoxy, F, Br, Cl, OH, CN, CO.sub.2 H, CF.sub.3, NO.sub.2, C.sub.1 -C.sub.4 carboalkoxy, NR.sup.10 R.sup.10, or NCOR.sup.11, benzyl optionally substituted with 1 to 3 groups selected from C.sub.1 -C.sub.4 alkyl or alkoxy, F, Br, Cl, OH, CN, CO.sub.2 H, CF.sub.3, NO.sub.2, C.sub.1 -C.sub.4 carboalkoxy, NR.sup.10 R.sup.10 or NCOR.sup.11, furfuryl, alkoxyalkyl and cyclic alkyl ethers with the proviso that R.sup.8 and R.sup.9 cannot both be aromatic. The term "cyclic alkyl" means a radical such as cyclohexyl which may be attached at the R.sup.8 and/or R.sup.9 position. PA1 R.sup.10 is selected independently from C.sub.1 to C.sub.4 alkyl. PA1 R.sup.11 is selected independently from H or C.sub.1 to C.sub.4 alkyl. PA1 Y is selected from the group consisting of unsubstituted or substituted trimethylene, tetramethylene or pentamethylene, exemplary substituents being divalent lower alkyl groups such as methylene, ethylene, propylene or butylene. PA1 X is selected from the group consisting of F, Cl, Br, OSO.sub.2 R.
Scheme 1, disclosed on page 9 of the European application, utilizes an imidazole as the starting compound and produces the antihypercholesterolemic agent as follows: ##STR2## wherein the substituents are as defined for Formula (I).
According to the scheme presented above, the esters of Formula (3) are hydrolyzed to the corresponding carboxylic acids of Formula (4) by methods well known in the art. The amides of Formula (5) are prepared by coupling the carboxylic acids of Formula (4) with a primary amine by amide bond forming reactions known in the art.
The problem is that the process represented by this reaction scheme is expensive because it is protracted and requires expensive omega haloalkanoates such as ethyl 5-bromopentanoate (step 1). Furthermore, the use of such omega haloalkanoates at the outset of a multistep synthesis increases the cost disadvantage of this process. A further disadvantage to the use of omega haloalkanoates is that many are lachrymators and/or irritants. Yet another disadvantage is that step 3 requires expensive dehydrating agents or requires two reaction steps via the acid chloride. Finally, as shown in the examples of the European application, the overall yield of the compound of Formula (5) is only modest.
This European application also describes an alternative reaction (Scheme 4) for preparing the amides of Formula (5) which in turn are used to prepare compounds of Formula (I). Alternative Scheme 4 is represented in the European application (p. 11) as follows: ##STR3## wherein the substituents are as described above.
Without teaching how, EP 0 372 445 Al suggests that alternatively the amides of Formula (5) can be prepared by the alkylation of Formula (1) or (2) with compounds of the formula: EQU M-(A')CONH.sup.6 (II)
wherein M is a halogen or tosylate group; A' is a moiety having one less methylene group than A (as described for Formula (I)); and R.sup.6 is as defined for Formula (I).
The European application merely alludes to this alternative alkylation step. It does not teach the preparation of M (A')CONHR.sup.6 (designated compound II), nor does it indicate the efficiency, yield, or economy of the suggested alkylating compound II, M (A')CONHR.sup.6.
We have found that tosylate esters of this formula (wherein M=tosylate group) decompose at ambient temperatures or more rapidly on heating. The comparative example herein shows that formation of the suggested tosylate esters of compound II occurs only slowly at room temperature. During the slow reaction at room temperature, the product begins to decompose even before the reaction is complete, thus yielding less than optimum amounts of product.
We have also found that the tosylate esters are difficult to purify and difficult to solidify. On the other hand, although the halogen compounds of Formula II (wherein M=halogen) can be derived from omega haloalkanoyl chlorides, these materials are expensive to produce and many are lachrymators. Furthermore, the chloro analogs alkylate only slowly and incompletely.
What is needed to produce a high overall yield of compounds of Formula (5) are reactive alkylating agents which are themselves rapidly formed and are capable of being obtained pure from inexpensive and readily available starting materials.